Thomas Wilson, M.D., Ph.D.

Administrative Contact

Michele Pushies

Areas of Interest

1) Mechanistic studies of DNA double-strand break repair: DNA double-strand breaks (DSBs) occur frequently and can be lethal if not repaired. Inappropriate repair can lead to chromosomal rearrangements. Understanding the dynamics of these events requires a detailed understanding of the molecular mechanisms of two competing DSB repair pathways, nonhomologous end-joining (NHEJ) and homologous recombination. We use genetic approaches, mainly in yeast, to identify novel components of these pathways and characterize their modes of action. Current focus is on DNA ligase IV, the lynchpin enzyme of NHEJ, resection of DSB ends, and nuclear influences on translocation frequency.

2) Impacts of DNA repair and transcription on copy number variant hotspots and fragile sites: The global effect of deficient DSB repair on genome stability has historically been difficult to assess, but high-throughput genome analysis tools, including microarrays and next-generation sequencing, now allow us to look in an unbiased manner at the relationships between DNA damage, repair, and chromosomal aberrations. Recent findings highlight that mammalian “fragile sites” are hotspots for copy number variant (CNV) formation under replication stress in a manner dependent on the active transcription of very large genes. We are working to describe the mechanisms by which transcription and replication interact throughout the cell cycle to promote genome structural alteration. This work has a strong bioinformatics component coupled with human cell and animal wet-lab experimentation.

3) The dynamic process of global gene expression: Our group is an active partner in the development of novel nascent RNA sequencing methods, especially Bru-seq, which allow us to examine the dynamic process of transcription and also the downstream stability of RNA transcripts. Major goals relate to understanding the factors that influence RNA polymerase transcription initiation and timely traversal through genes, and how these processes are both altered by and contribute to genomic DNA damage and mutagenic repair events.